Loss of the vasodilator, anti-thrombotic, and anti-inflammatory actions of endothelial-l-derived NO (EDNO) in atherosclerosis contribute to the clinical manifestations of coronary artery disease. Increased vascular oxidative stress has been linked to impaired EDNO action in atherosclerosis. Specifically, oxidized LDL, increased production of superoxide anion, and decreased availability of cellular antioxidant species may all contribute to impaired EDNO action. Prior studies investigating interactions between antioxidant species may all contribute to impaired EDNO action. Prior studies investigating interactions between antioxidants and EDNO have focused principally on lipid- soluble and extracellular antioxidants. However, the importance of intracellular redox status for EDNO action has been much less well characterized. Ascorbic acid (AA) and glutathione (GSH) are the principal water-soluble antioxidants in cells. We recently demonstrated that AA treatment improves EDNO-action in patients with atherosclerosis. We recently demonstrated that EDNO action is improved by oxothiazolidine-4-carboxylic acid (OTC), a cysteine pro-drug that augments cellular GSH stores. The goal of this project is to investigate the importance of cellular redox status in EDNO bioactivity in humans with coronary atherosclerosis with particular emphasis of the roles played by AA and GSH. We will use well-established methods to assess EDNO- dependent vasodilation including high-resolution brachial ultrasound, intra-arterial agonist infusion with venous occlusion plethysmography in the forearm of quantitative angiography and Doppler ultrasound in the coronary artery. Cellular redox state will be manipulated by acute or chronic administration of AA, OTC, EUK-8, an intracellularly-effective superoxide dismutase mimic, or lipoic acid, a thiol compound that reverse mitochondrial decay. The effects of these agents on cellular redox status will be confirmed by examining AA and GSH concentrations in vascular tissue collected intra-operatively and blood cells from patients. These parameters will be correlated with vasomoter responses. Since loss of EDNO action may contribute to the pathophysiology of ischemic syndromes in atherosclerosis, these studies have the potential to provide important insights for the management of coronary artery disease.